Stage IV

Cervical Cancer

Cervical cancer diagnosed as stage IV disease is commonly detected from an abnormal pelvic examination or symptoms produced by the patient’s cancer. Following a staging evaluation of cervical cancer, a stage IV cancer is said to exist if the cancer has extended beyond the cervix into adjacent organs, such as the rectum or bladder (stage IVA), or the cancer has spread to distant locations in the body which may include the bones, lungs or liver (stage IVB). Cervical cancer diagnosed in this stage is often difficult to treat, however a small minority of patients are cured of disease.

The following is an overview of the treatment of stage IV cervical cancer.  The information is intended to help educate you about treatment options and to facilitate a shared decision-making process with your treating physician.

Patients diagnosed with stage IV cervical cancer can be broadly divided into two groups. Patients with disease that is locally confined, but involves adjacent organs in the pelvis, such as the rectum and bladder, have localized stage IVA cervical cancer. Other patients have disease that has spread to distant organs, most commonly the bones, lungs or liver, and have metastatic stage IVB cervical cancer. Management of patients with metastatic stage IVB disease is aimed at control of symptoms and pain. After undergoing treatment for cervical cancer, your doctor will continue to follow you to check to see that the cancer has not returned or is not progressing.

Treatment of Localized Stage IVA Cervical Cancer

Stage IVA cervical cancer is currently best managed by a combination of radiation therapy and chemotherapy. Radiation therapy is treatment with high energy x-rays that have the ability to kill cancer cells. Radiation therapy can be administered by a machine that aims x-rays at the body (external beam radiation) or by placing small capsules of radioactive material directly near the cervix (internal or implant radiation). Most patients will receive both kinds of radiation therapy during their course of treatment. External beam radiation therapy for cervical cancer is administered on an outpatient basis for approximately 4 to 6 weeks.1,2

During or immediately following the external beam portion of radiation therapy, patients may also undergo an implant radiation procedure. Placing the radiation within the cervix allows a high dose of radiation to be delivered to the cancer, while reducing the radiation to the surrounding normal tissues and organs. During a procedure in the operating room, a small device is placed into the cervix and vagina and later is “loaded” with radioactive material. The radioactive material is left in place while the patient stays in the hospital for 1-3 days. This process may be performed once or twice during the course of treatment.

The addition of chemotherapy (anti-cancer drugs) has improved long-term outcomes in patients with cervical cancer..  Chemotherapy has the ability to kill cancer cells and make radiation therapy more effective at killing cancer cells. The strategy of administering chemotherapy concurrently with radiation treatment is appealing because chemotherapy and radiation therapy may act together to increase the killing of cancer cells. Chemotherapy may also destroy cells independently of radiation therapy. Clinical studies performed in patients with locally advanced cervical cancer utilizing concurrent chemotherapy and radiation therapy have improved remission rates and prolonged survival.1

Radiation therapy plus concomitant chemotherapy appears superior to radiation therapy alone. The 5-year survival rate of patients with stage IB, IIA, or IIB cervical cancer was 77% for patients treated with concurrent radiation therapy and chemotherapy, compared to only 50% for patients treated with radiation therapy alone. Concurrent chemotherapy and radiation therapy were well tolerated except for minor gastrointestinal and hematologic side effects, which were reversible.  Other clinical studies have confirmed that treatment of locally advanced cervical cancer with concurrent Platinol®-based chemotherapy and radiation therapy is superior to radiation therapy alone.1,2

Even with combination chemotherapy and radiation treatment, approximately 20-40% of patients with stage II cervical cancer experience recurrence of their cancer because cancer cells may have survived near the cancer despite the radiation therapy or small amounts of cancer may have spread outside the cervix and were not treated by the chemotherapy. These cancer cells cannot be detected and are referred to as micrometastases. The presence of these microscopic areas of cancer or surviving cancer cells can cause the relapses that follow treatment.

Treatment of Metastatic Stage IVB Cervical Cancer

Cervical cancer that has spread to distant organs and bones is difficult to treat and the main goal of treatment is to reduce symptoms and prolong survival.  Some patients are offered treatment with chemotherapy for the purpose of prolonging their duration of survival and alleviating symptoms from progressive cancer. Other patients are managed with efforts to reduce pain or bleeding, including local radiation therapy to affected parts of the body.

There is no good single chemotherapy approach that can improve the length of survival in patients with metastatic cervical cancer. Treatment with Platinol® can produce shrinkage in 15-25% of patients with metastatic cervical cancer. Many clinical trials have combined Platinol® with other chemotherapy drugs in hopes of improving cancer shrinkage and survival. Although these combination regimens can have more side effects, length of survival has not been improved over Platinol® alone. Unfortunately, these chemotherapies typically work for only a few months before the cervical cancer begins to grow again. Better treatment strategies are clearly needed.

Avastin (bevacizumab) is a targeted therapy that blocks a protein—VEGF—that plays a key role in the development of new blood vessels. This deprives the cancer of nutrients and oxygen and inhibits its growth. One pivotal clinical trial has demonstrated that the addition of Avastin to chemotherapy increases tumor shrinkage and improves survival among women with advanced cervical cancer.3

The progress that has been made in the treatment of cervical cancer has resulted from improved development of treatments in patients with more advanced stages of cancer and participation in clinical trials. Future progress in the treatment of cervical cancer will result from continued participation in appropriate clinical trials. Currently, there are several areas of active exploration aimed at improving the treatment of stage II cervical cancer.

Precision Cancer Medicines:  The purpose of precision cancer medicine is not to categorize or classify cancers solely by site of origin, but to define the genomic alterations in the cancers DNA that are driving that specific cancer.  Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed. Precision medicines are being developed for the treatment of cervical cancer and patients should ask their doctor about participating in clinical trials evaluating precision medicines and whether testing is appropriate.

Immunotherapy:  The immune system is an elaborate network of cells and organs that protect the body from infection.  The immune system is also part of the body’s innate disease-fighting capability to treat cancer.  With cancer, part of the problem is an ineffective immune system. The immune system recognizes cancer cells as foreign and up to a point can get rid of them or keep them in check.  Cancer cells are very good at finding ways to hide from, suppress, or wear out the immune system and avoid immune destruction.  The immune system may not attack cancer cells because it fails to recognize them as foreign and harmful.

The goal of immunotherapy is to help the immune system recognize and eliminate cancer cells by either activating the immune system directly, or by inhibiting mechanisms of suppression of the cancer.

General types of immunotherapy include interferon, interleukin, and colony stimulating factors (cytokines), which generally activate the immune system to attack the cancer. These general immunotherapies however are not specific and their activation of the immune system can cause severe side effects by attacking normal cells along with cancer cells.  Immunotherapy treatment of cancer has progressed considerably over the past 30 years and has evolved from a general to more precisely targeted immunotherapy treatment. Examples of precision immunotherapy include checkpoint inhibitors, CAR T cells, and vaccines.

In an attempt to improve the chance of cure, immunotherapies are being tested alone or in combination with chemotherapy in clinical trials.

Adoptive T-cell therapy (ACT) appears to provide anti-cancer responses among some patients with advanced cervical cancer for whom standard therapy has stopped working. The treatment includes the collection of a patient’s own type of immune cell (T-cell), that are engineered through laboratory processes to identify and attack cancer cells when infused back into the patient’s body.

An initial trial using T-cells from patients selected based upon their ability to fight certain strains of HPV associated with cervical cancer produced a complete response in some patients. Clinical trials are ongoing.4,5

Vaccines designed to stimulate the immune system against several different biologic pathways associated with incurable cervical can produce anti-cancer responses.  Researchers from Japan have conducted some studies to evaluate the effectiveness of using a “cocktail” vaccine, in which the patient’s immune system was stimulated to identify several different markers commonly found on cancer cells. In clinical trials evaluating 21 patients with cervical cancer some patients achieved a response to the vaccine and patients who demonstrated high levels of skin sensitivity to a pre test with the vaccine did significantly better.  Clinical trials are ongoing to evaluate this approach.

New Chemotherapy Regimens: Several newer chemotherapeutic drugs have demonstrated ability to kill cervical cancer cells in patients with advanced cancer. One area of active investigation is the development and exploration of single or multi-agent chemotherapy regimens as a treatment approach for patients with widespread cervical cancer. In particular, drugs such as paclitaxel, ifosfamide, Taxotere®, Navelbine®, Camptosar®, and Avastin appear to have promising activity against cervical cancer cells and are being tested alone or in combination with radiation and other anticancer agents in clinical trials.

Phase I Trials: New chemotherapy or immunotherapy drugs continue to be developed and evaluated in patients with recurrent cancers in phase I clinical trials. The purpose of phase I trials is to evaluate new anti-cancer medications in order to determine the safety and tolerability of a drug and the best way of administering the drug to patients.

Newer Radiation Techniques: External beam radiation therapy can be delivered more precisely to the cervix by using a special CT scan and targeting computer. This capability is known as three-dimensional conformal radiation therapy, or 3D-CRT. The use of 3D-CRT appears to reduce the chance of injury to nearby body structures, such as the bladder or rectum.

Next: Recurrent Cervical Cancer

References

1 https://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site

2 Duenas-Gonzalez A, Zarba JJ, Alcedo JC, et al. A phase III study comparing concurrent gemcitabine (Gem) plus cisplatin (Cis) and radiation followed by adjuvant Gem plus Cis versus concurrent Cis and radiation in patients with stage IIB to IVA carcinoma of the cervix. Presented at the 2009 annual meeting of the American Society of Clinical Oncology, May 29-June 2, 2009, Orlando, FL. Abstract CRA5507.

3 Tewari KS, Sill M, Long III HJ. Incorporation of bevacizumab in the treatment of recurrent and metastatic cervical cancer: a Phase III randomized trial of the Gynecologic Oncology Group. Presented at the 49th Annual Meeting of the American Society of Clinical Oncology. May 31-June 4, 2013; Chicago, IL. Abstract 3.

4 Takeuchi S, Shoji T, Kagabu M, et al. Phase 2 studies of multiple peptides cocktail vaccine for treatment-resistant cervical and ovarian cancer. Journal of Clinical Oncology. 2015; 33 (suppl; abstract 5567).

5 Stevanovic S, Draper L, Langhan M, et al. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells. Journal of Clinical Oncology, 2015; 10:33(4): 1543-1550. Doi: 10.1200/JCO.2014.58.9093.